This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population. Thus far, 697 subjects have been enrolled, including 403 recombinant immunoblot assay (RIBA) positives, 182 RIBA indeterminates, and 112 RIBA-negative controls. The early data have been published (New England Journal of Medicine 334:1691,1996) and the trends have remained the same over time. Unexpected findings were the high proportion (41 percent) of RIBA+ donors who admitted to prior (remote) intravenous drug use and the strong independent association between cocaine snorting and HCV positivity. Shared paraphernalia for snorting accompanied by epistaxis, may serve as a covert vehicle for parenteral viral transmission. Among anti-HCV+/RIBA-positive donors, 87 percent were persistently viremic, but 13 percent appeared to have recovered from prior HCV infection. In those with persistent infection who had liver biopsy, 86 percent had histologic evidence of mild to moderate chronic hepatitis, but only 6 percent had a severe histologic lesion despite prolonged infection, averaging 19 years from the time of exposure. Overall, HCV infection in this cohort was generally asymptomatic and clinically benign. Despite an association of HCV with sexually promiscuous practices, we found no evidence for sexual transmission to the specific partners of 116 HCV-infected individuals. The study continues to follow the natural history HCV infection and is now focusing on histologic progression as assessed in liver biopsies obtained at 5-year intervals. New emphasis is being placed on studies of cell-mediated immune responses to HCV and of treatment responses.